CH663411A5 - INDOLE DERIVATIVES USEFUL AS MEDICINES. - Google Patents

Description

The invention relates to indole derivatives useful as medicaments and compounds for their preparation. These derivatives and the pharmaceutical compositions containing them are useful in particular in the treatment of migraine.

45 It is known that migraine pain is mainly of vascular origin and that it is caused by excessive dilation of the cranial vascular system. Known migraine treatments include the administration of compounds with vasoconstrictive properties such as ergotamine. However, ergotamine is a non-selective vasoconstrictor which constricts blood vessels throughout the body and has unwanted side effects which can be dangerous. Migraine can also be treated by administering a pain reliever, usually in combination with an antiemetic, but these treatments are of limited value. 55 We are therefore looking for an effective and safe drug for the treatment of migraine that can be used either prophylactically or to relieve established headaches, and a compound having selective vasoconstrictor activity fulfilling this role.

We have discovered a group of indole derivatives having a potent and selective vasoconstrictive acti-60.

The subject of the invention is indoles corresponding to the general formula (I):

R1R2nso2A

AlkNR3R4

(I)

3

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in which

R 1 represents a hydrogen atom or a C 1-6 alkyl or C 3-6 alkenyl radical;

R2 represents a hydrogen atom or a C1-3 alkyl, C3.6 alkenyl, phenyl-CM alkyl or C5.7 cycloalkyl radical;

R3 and R4, which may be similar or different, represent a hydrogen atom or a Cw or 2-propenyl alkyl radical or R3 and R4 together form an aralkylidene radical;

Alk represents an alkylene chain containing two or three carbon atoms which may be unsubstituted or substituted by not more than two C1-3 alkyl radicals, and

A represents an alkylene chain containing two to five carbon atoms which may be unsubstituted or substituted by not more than two C 3 alkyl radicals,

and their physiologically acceptable salts and their solvates (for example their hydrates).

The invention covers all the optical isomers of the compounds of general formula (I) and their mixtures, including their ra-cemic mixtures.

According to the general formula (I), the alkyl radicals of this formula can be straight or branched chain alkyl radicals containing 1 to 3 carbon atoms, or, in the case of Rls I to 6 and preferably 1 to 3 atoms carbon. Examples of alkyl radicals include methyl, ethyl, propyl, and isopropyl. The alkenyl radicals preferably contain 3 or 4 carbon atoms and examples are the propenyl and butyl radicals. It should be noted that when Rj or R2 is an alkenyl radical, the double bond must be separated from the nitrogen atom by at least one methylene radical. Cycloalkyl radicals preferably contain 5 or 6 carbon atoms and examples are the cyclopentyl and cyclohexyl radicals. The alkyl fragments of the phenyl-alkyl radicals preferably contain 1 or 2 carbon atoms, as is for example the case of the benzyl and phenethyl radicals. The aralkylidene radical is preferably an aryl-methylidene radical such as benzylidene.

In the compounds of general formula (I), it is preferred that at least one of R 1 and R 2 represents a hydrogen.

A is preferably an unsubstituted alkylene chain containing 2 to 5 carbon atoms, in particular 2 or 3 carbon atoms. Alk is preferably an unsubstituted alkylene chain, in particular an unsubstituted alkylene chain containing 2 carbon atoms.

A preferred category of the compounds represented by the general formula (I) is that in which R 1 represents a hydrogen atom or a C 1 -C 6 alkyl radical and R 2 represents a hydrogen atom or a C 1 -C 3 alkyl or phenyl-alkyl radical. in CM.

Another preferred category of the compounds represented by the general formula (I) is that in which A represents the radical -CH2CH2-.

Another preferred category of compounds is that in which, in the general formula (I), R3 and R4, which may be similar or different, each represent a hydrogen atom or a C 1 -C 3 alkyl radical.

A preferred category of the compounds covered by the general formula (I) is that represented by the general formula (la):

R3a and R4a, which may be similar or different, each represent a hydrogen atom or a methyl or ethyl radical, and n represents 2 or 3,

and their physiologically acceptable salts and their sol-vatation products (eg their hydrates).

A particularly preferred category of the compounds according to the invention is that represented by the general formula (Ib):

RlaE2aNS02'C1,2l,

H

in which

R] a represents a hydrogen atom or a C1-3 alkyl radical;

R2a represents a hydrogen atom or a C1-C3 alkyl or phenyl-C1-2 alkyl radical;

RlbNHS02 (CH2) 2

'(CH2J2NR3bR4b

(CH2> 2NR3aR4;

(the)

(Ib)

in which

R 5, b represents a hydrogen atom or a C 3 alkyl radical, and R 3 b and R 4 b, which may be similar or different, each represent a hydrogen atom or a methyl or ethyl radical,

and their physiologically acceptable salts and their sol-vation products (eg their hydrates).

In the compounds of formula (Ib), it is preferred that the total number of carbon atoms in R3b and R4b does not exceed 2 and better than R3b and R4b each represent a methyl radical.

Preferred compounds according to the invention include: 3- [2- (ethylamino) ethyl] -N-methyl] -1 H-indole-5-ethanesulfon-amide;

N-methyl-3- [2- (methylamino) ethyl] -1 H-indole-5-ethanesulfon-amide;

3- (2-aminoethyl) -N-methyl-1H-indole-5-ethanesulfonamide; 3- [2- (dimethylamino) ethyl] -1H-indole-5-ethanesulfonamide;

3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-ethanesul-fonamide;

and physiologically acceptable salts and solvates (eg hydrates) of these compounds.

The suitable physiologically acceptable salts of the indoles of general formula (I) include the acid addition salts formed with organic or mineral acids, for example hydrochlorides, hydrobromides, sulfates, fumarates, maleates and succinates. Other salts may be useful in the preparation of the compounds of general formula (I), for example the adducts of creatininesulfate type and Oxalates.

It should be noted that the invention covers the other physiologically acceptable equivalents of the compounds according to the invention, that is to say the physiologically acceptable compounds which are trans-formed in vivo into the parent compound. Examples of such equivalents include physiologically acceptable derivatives having a labile N-acyl radical, such as an N-acetyl derivative.

The compounds of the invention cause selective constriction of the carotid arterial bed in anesthetized dogs while having a negligible effect on blood pressure. The selective vasoconstrictor action of the compounds of the invention has been demonstrated in vitro.

The compounds of the invention are useful in the treatment of pain resulting from dilation of the cranial vascular system, in particular migraine and Horton's vascular headache. 55 In particular, the compounds of formula (Ib) previously defined have proved to be very selective vasoconstrictors and of extremely powerful action. The compounds of general formula (Ib) are rapidly absorbed from the gastrointestinal tract and are suitable for oral or rectal administration. The compounds of formula (Ib) do not exhibit toxic or undesirable effects in rats at doses up to 6 mg / kg. At the doses at which the compounds of formula (I) are effective in the treatment of migraine, the compounds have no noticeable effect on blood pressure and heart rate nor any noticeable bronchoconstrictor effect on the 65 lungs.

The invention also provides a pharmaceutical composition suitable for use in medicine which comprises at least one compound of formula (I) or one of its physiologically accepted salts.

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4

wheat or solvates (eg hydrate) and which is presented for administration by any suitable route. These compositions can be prepared in a conventional manner by using one or more carriers or excipients suitable in pharmacy.

The compounds of the invention can therefore be presented for oral, buccal, parenteral or rectal administration or in a form suitable for administration by inhalation or insufflation. Preferred are the compositions of the compounds of the invention suitable for oral administration.

For oral administration, the pharmaceutical compositions can be in the form, for example, of tablets or capsules prepared in a conventional manner with excipients suitable in pharmacy such as binders (for example pregelatinized corn starch, polyvinylpyrrolidone or 'hydroxypropylmethylcellulose); fillers (for example lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (for example magnesium stearate, talc or silica); disintegrants (for example potato starch, sodium starch glycolate or croscarmellose); or wetting agents (for example sodium lau-rylsulfate). The tablets can be coated according to methods well known in the art. Liquid preparations for oral administration can be in the form, for example, of solutions, syrups or suspensions or can be presented in the form of a dry product to be taken up with water or another suitable vehicle before use. These liquid preparations can be prepared in a conventional manner with pharmaceutically acceptable additives, such as suspending agents (for example sorbitol syrup, cellulose derivatives, for example hydroxypropylmethylcellulose or hydrogenated edible fats); emulsifying agents (for example lecithin or gum arabic); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils), and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid) . Liquid preparations can also contain conventional buffers, flavoring agents, colors and sweeteners as needed.

For buccal administration, the compositions can be in the form of tablets or lozenges prepared in a conventional manner.

The compounds of the invention can be presented for parenteral administration by injection, for example by injection proper or continuous infusion. The injectable presentations can be in the form of unit doses, for example in ampoules or multidose containers with the addition of a preservative. The compositions may be in the form of suspensions, solutions or emulsions in oily or aqueous vehicles and may contain preparation agents, such as suspension, stabilization and / or dispersion agents and / or agents adjusting the tone of the solution. Otherwise the active ingredient may be in the form of a powder to be reconstituted before use with an appropriate vehicle, for example sterile pyrogen-free water.

The compounds of the invention can also be presented in the form of rectal compositions such as suppositories or enemas to keep, containing for example conventional bases for suppositories, such as cocoa butter or other glycerides.

For administration by inhalation, the compounds of the invention are sprayed in the form of an aerosol from pressurized packaging, by using a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetra- fluoroethane, carbon dioxide or another suitable gas, or are administered with a nebulizer. In the case of a pressurized aerosol, the unit dose can be obtained by using a metering valve. Capsules or cartridges, for example in gelatin, intended for use in an inhaler or an insufflator, can be prepared to contain a powder mixture of a compound of the invention and of a suitable powder base, such as than lactose or starch.

A proposed dosage of the compounds of the invention for oral, parenteral, rectal or buccal administration to humans (for an average body weight of around 70 kg for example) in the treatment of migraine is 0.1 to 100 mg of active ingredient per unit dose to be administered for example one to four times a day. It should be noted that the usual changes in dosage may be necessary depending on the age and weight of the patient as well as the severity of the condition to be treated.

For oral administration, a unit dose preferably contains 2-50 mg of active ingredient. A unit dose for parenteral administration preferably contains 0.2 to 5 mg of active ingredient.

Aerosol presentations are preferably designed so that each dose or "puff" delivered by a pressurized aerosol container contains 0.2 to 2 mg of a compound of the invention and that each dose administered by capsules or cartridges,

with an insufflator or inhaler, contains 0.2 mg to 20 mg of a compound of the invention. The overall daily dose by inhalation is in the range of 1 mg to 100 mg. The administration may be repeated several times a day, for example 2 to 8 times, with the administration each time, for example, of 1, 2 or 3 doses.

The compounds of the invention may, if desired, be administered in combination with one or more other therapeutic agents such as analgesics, anti-inflammatory agents and anti-nausea agents.

According to another aspect of the invention, the compounds of general formula (I) and their physiologically acceptable salts and their solvates (for example hydrates) can be prepared according to the general methods indicated below.

In the following methods, R1; R2, R3, R4, A and Alk are as defined for the general formula (I) unless otherwise indicated.

According to a general process (A), the compounds of general formula (I) can be prepared by cyclization of compounds of general formula (II):

35 R1R2nso2A

i (ii)

"^: ^ / ^ JHN = CHCH2AlkQ

in which Q is the radical NR3R4 or a corresponding protected derivative or is a labile group such as a halogen atom (for example of chlorine or of bromine) or an acyloxy radical which can derive from a carboxylic or sulphonic acid, such than an acetoxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy, p-nitro-benzoyloxy, p-toluenesulfonyloxy or methanesulfonyloxy radical.

The reaction can conveniently be carried out in aqueous or non-aqueous reaction media and at a temperature of 50 to 200 ° C, preferably 50 to 125 ° C.

Particularly practical embodiments of the method are described below.

When Q is the radical NR3R4 (or a protected derivative thereof), the process is desirably carried out in the presence of a polyphosphate ester in a reaction medium which may comprise one or more organic solvents, preferably halogenated hydrocarbons such as chloroform, dichlorome-thane, dichloroethane, dichlorodifiuoromethane or their mixtures. The polyphosphate ester is a mixture of esters which can be prepared from phosphorus pentoxide, diethyl ether and chloroform according to the process described in "Reagents for Organic Synthesis", (Fieser and Fieser, John Wiley and Sons, 1967).

Otherwise, the cyclization can be carried out in an aqueous or non-aqueous reaction medium in the presence of an acid catalyst. When an aqueous medium is used, it may be an aqueous organic solvent such as an aqueous alcohol (for example methanol, ethanol or isopropanol) or an aqueous ether (for example dioxane or tetrahydrofuran ) as well as mixtures of such solvents, and the ca

5

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The acid analyzer can, for example, be a mineral acid, such as hydrochloric acid or concentrated sulfuric acid, or an organic acid such as acetic acid. In certain cases, the acid catalyst can also constitute the reaction solvent. In an anhydrous reaction medium which can comprise one or more alcohols or ethers (for example as previously described), or esters (for example ethyl acetate), the acid catalyst is generally a Lewis acid, such as trifluoride. boron, zinc chloride or magnesium chloride.

When Q is a labile group, such as a chlorine or bromine atom, the reaction can be carried out in an aqueous organic solvent, such as an aqueous alcohol (for example methanol, ethanol or isopropanol) or an aqueous ether (for example dioxane or tetrahydrofuran) in the absence of a catalyst consisting of a mineral acid, practically at a temperature of 20 to 200 ° C, preferably from 50 to 125 ° C. This process forms a compound of general formula (I) in which R3 and R4 are both hydrogen atoms.

According to a particular embodiment of this process, the compound of general formula (I) can be prepared directly by reaction of a compound of general formula (III):

R1R2nso2A

AlkY

R1R2NS02A

(III)

nhnh,

or of a salt (for example the hydrochloride) thereof, with a compound of formula (IV):

OHCCHjAlkQ

(IV)

(in which Q is as previously defined) or a protected salt or derivative thereof such as an acetal, for example a dialkyl acetal or a cyclic acetal, for example formed with an alkyl orthoforate or a suitable diol (or protected in the form of a bisulphite addition complex), using suitable conditions as just described for the cyclization of a compound of general formula (II) (The Fischer-Indole Synthesis, B. Robinson, p. 488 - Wiley 1982). In this embodiment, the compounds of general formula (II) can be formed as intermediates and can be either isolated before cyclization, or reacted in situ to form the desired compounds of general formula (I).

The compounds of general formula (II) can, if desired, be isolated as intermediates by reaction of a compound of formula (III) or of a corresponding protected salt or derivative thereof, with a compound of formula (IV ) or a corresponding protected salt or derivative, in a suitable solvent, such as an aqueous alcohol (for example methanol) or an aqueous ether (for example dioxane) at a temperature for example of 20 to 30 ° C. If l 'an acetal of a compound of formula (IV) is used, it may be necessary to carry out the reaction in the presence of an acid (for example acetic acid or hydrochloric acid).

The compounds of formula (III) constitute another aspect of the invention. In turn, they can be prepared according to conventional processes for the preparation of a hydrazine, for example the reduction of the corresponding nitro compound, to form the amino derivative, by catalytic hydrogenation, then the reaction with sodium nitrite in the presence of a mineral acid (for example hydrochloric acid) to form a diazonium salt which is then reduced, for example with stannous chloride, to the desired hydrazine of formula (III).

Another general process (B) for the preparation of the compounds of general formula (I) comprises the reaction of a compound of general formula (V):

(v)

(in which Y is an easy-to-move group) or a corresponding protected derivative, with a compound of formula R3R4NH. This displacement reaction can be carried out in a practical manner on the compounds of general formula (V) in which the substituent group Y is a halogen atom (for example chlorine, bromine or iodine); an OR5 radical which is, for example, an acyloxy radical (which can be derived from a carboxylic or sulphonic acid) such as an acetoxy, chloroacetoxy, dichloroacetoxy, trifluoroacetoxy or p-nitrobenzyloxy, p-toluenesulfonyloxy or methanesulfonyloxy radical; or an N + R'R "R '" E ~ radical, where R', R "and R '" may be the same or different and each represents a C ^ alkyl radical and E ~ represents an anion such as an ion halide, for example a chloride, bromide or iodide ion.

The displacement reaction can conveniently be carried out in an inert organic solvent (optionally in the presence of water), examples of which include alcohols, for example ethanol: cyclic ethers, for example dioxane or tetrahydrofuran; acyclic ethers, for example diethyl ether; esters, for example ethyl acetate; amides, for example N, N-dimethylformamide, and ketones, for example acetone, methyl ethyl ketone or methyl isobutyl ketone. The process can be carried out at a temperature for example of - 10 to + 150 ° C., preferably of 30 to 50 ° C.

The compounds of formula (V), where Y is a halogen atom, can be prepared by reacting a hydrazine of formula (III) with an aldehyde (or a corresponding protected derivative) of formula (IV) where Q is a halogen atom, in an aqueous alcohol (for example methanol) or an aqueous ether (for example dioxane) containing an acid (for example acetic or hydrochloric acid) or by reaction of a compound of general formula ( V) where Y is a hydroxy radical, with the appropriate phosphorus trihalide or with N-bromosuccinimide or triphenylphosphine in tetra-40 hydrofuran. The intermediate alcohol, in which Y is a hydroxy radical, can also be used to prepare the compounds of formula (V) where Y is an OR5 radical, by acylation with the appropriate activated species (for example an anhydride or the chloride of sul-fonyle) using conventional techniques. The intermediate alcohol 45 can be prepared by cyclization of a compound of formula (II) in which Q is a hydroxy radical (or a corresponding protected derivative) under standard conditions.

The compounds of formula (V) where Y represents an N + R'R "R '" E ~ radical can be prepared from the corresponding tertiary amine so by reaction with an alkylating agent, for example as described in general process (E) below.

The compounds of general formula (I) can easily be prepared according to another general process (C) comprising the reduction of a compound of general formula (VI):

55 R1R2nso2A1

(VI)

60

where W is a radical which can be reduced to form the desired AlkNR3R4 radical or to form a protected derivative of the radical AlkNR3R4, and A1 represents the radical A previously defined or a radical which can be reduced to form the radical A, or a salt or 65 derivative thereof protected protected.

The radicals A1 which can be reduced to form the radical A required include the corresponding unsaturated radicals, such as the C2.5 alkenyl radicals.

663411

6

The necessary Alk and NR3R4 radicals can be formed according to reduction stages carried out separately or simultaneously in any suitable manner.

The radicals which can be reduced to the radical Alk include the corresponding unsaturated radicals and the corresponding radicals containing one or more hydroxy radicals or carbonyl functions.

The radicals which can be reduced to the NR3R3 radical include the nitro, azido, hydroxyimino, nitrile and amide radicals.

Examples of the radicals represented by the substituent radical W therefore include TNO2 (where T is an Alk radical or an alkenyl radical corresponding to the Alk radical); AlkN3; AlkNR3COR'4; —COCONR3R3; (CHR5) sCHR6CN; CHR6COZ; (ŒR5) sCR6 = NOH; CH (OH) CHR6NR3R4; COCHReZ (where R5 and R6, which may be similar or different, each represents a hydrogen atom, or a C1-3 alkyl radical, Z is an azido N3 radical or the NRT3R4 radical or a corresponding protected derivative, x is zero or 1 and R'4 is a hydrogen atom or a radical such that —CH2R'4 is the radical R4, or R'4 is the radical ORç where Rç is an alkyl or aralkyl radical).

Radicals which can be reduced to form the radical NR3R4 where R3 and R4 are both hydrogen include the radicals nitro, azido, hydroxyimino and nitrile. The reduction of a nitrile radical produces the CH2NH2 radical and therefore provides a methylene radical of the Alk group.

A compound of general formula (I), where R, is a hydrogen atom, can also be prepared by reduction of a corresponding compound of general formula (I), where R4 is a benzyl radical, for example with hydrogen in the presence of a catalyst, for example 10% palladium-on-carbon.

The required NR3R4 radical, where R3 and / or R | are other than hydrogen, can be prepared by reduction of a nitrile (CHRjjjCHRöCN or an aldehyde (CHR5) xCHR6CHO (where R5, R6 and x are as defined above) in the presence of an amine R3R, NH.

A particularly suitable process for preparing a compound of formula (I), where R3 and / or R, are other than hydrogen, is alkylation by reduction of the corresponding compound where R3 and / or R4 represent hydrogen, with an aldehyde or an appropriate ketone (e.g. formaldehyde or acetone) in the presence of an appropriate reducing agent. In certain cases (for example to introduce the radical R4 when it represents a methyl), the aldehyde (for example formaldehyde) can be condensed with the primary amine and the intermediate thus formed can then be reduced with a reducing agent appropriate.

The required NR3R4 radical, where R3 and / or R4 are other than hydrogen, can also be prepared by reduction of a corresponding amide, for example AlkNR3COR'4 (where R'4 is as previously defined).

The reduction can be carried out according to conventional methods, for example by catalytic hydrogenation or by the use of a reducing agent, such as a borohydride or cyanoborohydride of an alkali metal or of an alkaline earth metal or of a metal hydride. The reduction can conveniently be carried out in an organic reaction medium which may include one or more solvents. Suitable solvents include alcohols, for example ethanol or propanol; cyclic ethers, for example dioxane or tetrahydrofuran; acyclic ethers, for example diethyl ether; amides, for example dimethylformamide, and esters, for example ethyl acetate, and nitri-les, for example acetonitrile.

It will be noted that the choice of reducing agent and of the reaction conditions depends on the nature of the radicals W and A1.

Suitable reducing agents which can be used in the above process for the reduction of the compounds of formula (VI) where W represents for example the radicals TN02, AlkN3, (CHRj) xCHR6CN, (CHR5) xCR6 = NOH, CH (OH) CHR6NR3R4 (where T, R5 and R6 and x are as previously defined) comprise hydrogen in the presence of a metal catalyst, for example Raney nickel, or a noble metal catalyst, such as platinum, l platinum oxide, palladium or rhodium, which can for example be attached to a support consisting of carbon, kieselguhr or alumina. In the case of Raney nickel, hydrazine can also be used as a source of hydrogen. This process can conveniently be carried out in a solvent, such as an alcohol, for example ethanol; an ether, for example dioxane or tetrahydrofuran; an amide, for example dimethylformamide; or an ester, for example ethyl acetate, at a temperature of -10 to + 50 ° C, preferably of -5 to + 30 ° C.

The reduction process can also be carried out on compounds of general formula (VI) where W represents for example the groups TN02) CH (OH) CHR6NR3R4 or COCHR6 (where T, R6 and Z are as previously defined) by using a alkali metal or alkaline earth metal borohydride or cyanoborohydride, for example sodium or calcium borohydride or cyanoborohydride, this process being able to be practically carried out in an alcohol, such as propanol or ethanol, or a nitrile , such as acetonitrile, and at a temperature of 10 to 100 ° C, preferably 50 to 100 ° C. In some cases, the reduction using a borohydride can be carried out in the presence of cobaltous chloride.

The reduction of the compounds of general formula (VI) where W represents for example the radicals TN02, AlkN3, AlkNR3COR'4, CHR6COZ, (CHR5) xCR6 = NOH, CH (OH) CHR6NR3R4, -COCONR3R4 and COCHR6Z (where R, R ' 4, Rs, R & Z and x are as defined above) can also be carried out by using diborane or a metal hydride such as lithium hydride and aluminum. This process can be carried out in a solvent, for example an ether such as tetrahydrofuran, and conveniently at a temperature of -10 to + 100 ° C, preferably 50 to 100 ° C.

A particular embodiment of the general process (C) comprises the reduction of a compound of general formula (VI) where W is the radical CHR6CN, for example by catalytic reduction with hydrogen in the presence of a catalyst, such as palladium-on-carbon or rhodium-containing alumina, optionally in the presence of an amine HNR3R4 or, to produce a compound where R3 and R, are both hydrogen, by using aluminum hydride and lithium in the absence of 'an amine.

Suitable reducing agents which can be used in the reduction of the radical A1 include hydrogen in the presence of a metal catalyst. Suitable metal catalysts and process conditions are as described for the reduction of the radical W.

The starting materials or the intermediate compounds of general formula (VI) can be prepared according to methods analogous to those described in published patent application GN N ° 2035320 and in "A Chemistry of Heterocyclic Compounds - Indoles Part II", chapter VI , edited by WJ Houlihan (1972), Wiley Interscience, New York.

A compound of general formula (VI) where W is the radical AlkNHCOR'4 can be prepared by acylation of the corresponding unsubstituted amine using conventional techniques.

The Fischer indolic cyclization process can be used to prepare a compound of general formula (VI) where W is the radical (CHR5) XCHR6CN or CHR5CHR6N02 in a conventional manner.

A compound of formula (VI), where A1 is an alkenyl radical containing 2 to 5 carbon atoms, can be prepared by reaction of a corresponding 5-halo indole of general formula (VTI)

Hai where W is as defined for the general formula (VI) and Hai is a halogen atom, for example bromine or iodine, with an alkene

5

10

15

20

25

30

35

40

45

50

55

60

65

7

663 411

suitable of formula R | R2NSO2 (CH2) pCH = CH2 (where p represents 0,1,2 or 3) in the presence of a catalyst such as a palladium (II) salt, for example acetate, and a phosphine , for example triphé-nylphosphine or tri-o-tolylolphosphine, with a tertiary nitrogen base, such as triethylamine or tri-n-butylamine. The reaction can conveniently be carried out in a solvent, for example acetonitrile, methanol or dimethylformamide, and at a temperature of 75 to 160 ° C. Otherwise, the compounds of formula (VI) can be prepared by reaction d 'an indole-5-carbaldehyde of general formula (VIII)

0hc (ch2) q xso2a

AlkNR3R4

NOT '

h in which X represents a labile group, with an amine of general formula (X):

R.

V

r,

/

NH

Examples of suitable labile groups X in the compound of general formula (IX) include a halogen atom (for example a fluorine, chlorine or bromine atom) or a radical OR7 where R7 represents a hydrocarbyl radical such as aryl radical, for example phenyl. The aryl radical may be unsubstituted or substituted by one or more substituents, such as halogen atoms; or nitro radicals; cyano; amino; alkyls, for example methyl; alkoxy, for example methoxy; acyl, for example acetyl, and alkoxycarbonyl, for example ethoxycarbonyl. The labile group represented by X is preferably a phenoxy group.

The reaction is conveniently carried out in the presence of a solvent and can be carried out in an aqueous or non-aqueous reaction medium.

The reaction medium can comprise one or more organic solvents such as ethers, for example dioxane or tetrahydrofuran; amides, for example N, N-dimethylformamide or N-methylpyrrolidone; alcohols, for example methanol or ethanol; esters, for example ethyl acetate; nitriles, for example acetonitrile; halogenated hydrocarbons, for example dichloromethane; and tertiary amines, for example triethylamine or pyridine, optionally in the presence of water. In some cases, the amine of formula (IX) can itself serve as a solvent.

If desired, the aminolysis can be carried out in the presence of a base, such as a tertiary amine (eg triethylamine or pyridine); an alcoholate (for example sodium tert.-butoxide) or a hydride (for example sodium hydride).

The reaction can conveniently be carried out at a temperature of -20 ° C to + 150 ° C.

The compounds of general formula (IX) constitute another aspect of the invention. They have a powerful and selective vasoconstrictor activity as described above for the compounds of general formula (I).

The starting materials of general formula (IX) where X represents an OR7 radical can be prepared for example by reduction of a compound of general formula (XI)

xso2a

(VIII)

where W is as defined for the general formula (VI) and q is an integer from 1 to 4,

with, for example, a suitable dialkyl phosphonate, under standard conditions.

The compounds of general formula (I) can be prepared according to another general process (D) which comprises the reaction of an indole of general formula (IX):

(IX)

(X)

(XI)

[where W is as defined for formula (VI)] or a corresponding protected salt or derivative.

The reduction can be carried out analogously to the general process (C) and examples of the appropriate groups W and details of the reaction conditions are given with respect to the general process (C).

A compound of formula (IX) where W represents a halogen atom can be prepared for example by reaction of the corresponding sulfonic acid derivative and a salt thereof with a halogenating agent, such as a halide or a phosphorus oxyhalide, in an inert organic solvent, for example phosphorus pentachloride in dichloromethane. A sulfonic acid of formula (IX) where X is OH can be prepared, for example by an acid or base catalyzed hydrolysis of an ester of formula (IX) (i.e. a compound where X represents the radical 0R7).

The compounds of general formula (XI) can be prepared by methods analogous to those described in British patent application published No. 2035310 and in "A chemistry of He-terocyclic Compounds - Indoles Part II", chapter VI, published by WJ Hamilton (1972) Wiley Interscience, New York, as well as in GB patent application No. 8315564.

According to another general method (E), a compound of formula (I) according to the invention or a corresponding protected salt or derivative can be transformed into another compound of the invention according to conventional procedures.

For example, a compound of general formula (I), where one or more of R1, R2, R3 and R4 are alkyl radicals, can be prepared from the corresponding compounds of formula (I) where one or more of R ,, R2, R3 and R4 represent hydrogen atoms, by reaction with an appropriate alkylating agent such as a compound of formula RXL where Rx represents the radical Rh R2, R3 or R4 desired and L represents a labile group such than a halogen atom or a tosylate radical, or a sulfate (Rx) 2SO4. So the alkylating agent can be for example an alkyl halide (for example methyl or ethyl iodide), an alkyl tosylate (for example methyl tosylate) or a dialkyl sulfate (for example dimé-thyle sulfate). The alkylation reaction is carried out in a practical manner in an inert organic solvent such as an amide (for example dimethylformamide), an ether (for example tetrahydrofuran) or an aromatic hydrocarbon (for example toluene) preferably in the presence of a base. Suitable bases include, for example, alkali metal hydrides, such as sodium or potassium hydride, alkali metal amides, such as sodium amide, alkali metal carbonates, such as sodium carbonate and alkali metal alcoholates, such as sodium or potassium methylate, ethylate or tert.-butoxide. When an alkyl halide is used as the alkylating agent, the reaction can also be carried out in the presence of an acid scavenger, such as propylene or ethylene oxide. It is also possible to use a catalyst such as tetrabutylammonium fluoride. The reaction can conveniently be carried out at a temperature of - 20 ° C to + 100 ° C.

65 The compounds of formula (I), where R represents a C3.6 alkenyl radical, R2 represents a C3_6 alkenyl radical, phenyl-CM alkyl or C5.7 cycloalkyl and / or one of R3 and R4 or both represent a propenyl radical, can be prepared sem

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blable by using an appropriate compound of formula RXL or (RJ2S04.

According to another general process (F), a compound of general formula (I) according to the invention, or a salt thereof, can be prepared by subjecting a protected derivative of general formula (I) or one of its salts to a reaction to remove the protective group (s).

Thus, at an early stage in the reaction sequence for the preparation of a compound of general formula (I) or of a salt thereof, it may be necessary or desirable to protect one or more sensitive radicals of the molecule to avoid reactions unwanted side effects. For example, it may be necessary to protect the NR3R4 radical, where R3 and / or R4 represent a hydrogen, by fixing a proton or with a radical which is easy to remove at the end of the reaction sequence. Such radicals can include, for example, aralkyl radicals, such as benzyl, diphenylmethyl or triphenylmethyl: or acyl radicals such as N-benzyloxycar-bonyl or tert.-butoxycarbonyl or phthaloyl.

In some cases, it may also be desirable to protect the indole nitrogen, for example with an aralkyl radical such as benzyl.

The subsequent cleavage of the protective group (s) can be carried out according to conventional procedures. It is thus possible to cleave an aralkyl radical, such as benzyl, by hydrogenolysis in the presence of a catalyst (for example palladium on carbon) or of sodium and liquid ammonia; an acyl radical such as N-benzyloxycarbonyl can be removed by hydrolysis with, for example, hydrobromic acid in acetic acid or by reduction, for example, by catalytic hydrogenation. The phthaloyl radical can be eliminated by hydrazi-nolysis (for example by treatment with hydrazine hydrate) or by treatment with a primary amine (for example methylamine).

It will be noted that in some of the general methods (A) to (E) described above, it may be necessary or desirable to protect from sensitive radicals of the molecule as described above. Thus, a reaction stage comprising a deprotection of a protected derivative of general formula (I) or of a salt thereof can be carried out after any of the methods (A) to (E) previously described.

Therefore, according to another aspect of the invention, the following reactions (G) in an appropriate context can, if it is necessary and / or desirable, be carried out after any of the methods (A) to (E):

(1) removal of any protecting group, and

(2) conversion of a compound of general formula (I) or of a salt thereof into a physiologically acceptable salt or a solvate (for example a hydrate) thereof.

When it is desired to isolate a compound of the invention in the form of a physiologically acceptable salt, for example an acid addition salt, the free base of general formula (I) can be treated with an appropriate acid ( for example succinic or hydrochloric acid) preferably in an equivalent amount in a suitable solvent (for example aqueous ethanol).

The starting materials or the intermediate compounds for the preparation of the compounds according to the invention can be prepared according to conventional methods analogous to those described in the published GB patent application No. 2035310.

As they are used as the last main stage of the preparation sequence, the general methods indicated above for the preparation of the compounds of the invention can also be used to introduce the desired radicals in an intermediate stage of the preparation of the compound required. For example, the radical required in position 5 can be introduced either before or after the cyclization forming the indole nucleus. It should therefore be noted that, in these multi-stage processes, the order of the reactions must be chosen so that the reaction conditions have no effect on the radicals present in the molecule which is desired in the product final.

The invention is further illustrated by the following nonlimiting examples. All temperatures are at 0 C. The "Hyflo" is a filtration aid. Reactivials are 4 ml thick-walled glass bottles with a screw cap and a teflon-coated disc supplied by Pierce and Warriner (UK) Ltd. Chromatography is carried out either conventionally with silica gel (Merck, Kiesel-gel 60, Art. 7734) or by "flash" chromatography (WC Still, M. Kahn and A. Mitra, J. Org. Chem. 2923 , 43.1978) on silica (Merck 9385) and thin layer chromatography (TLC) on silica (Macherly-Nagel, Polygram) unless otherwise indicated. The following abbreviations are assigned to the eluent used for chromatography and TLC.

(A) Methylene chloride-ethanol-ammonia (0.88) 50/8/1

(B) Methylene chloride-ethanol-ammonia (0.88) 100/8/1

(C) Methylene chloride-ethanol-ammonia (0.88) 60/8/1

(D) Methylene chloride-ethanol-ammonia (0.88) 25/8/1

(E) Methylene chloride-ethanol-ammonia (0.88) 200/8/1

(F) Methylene chloride-ethanol-ammonia (0.88) 750/10/1

(G) Methylene chloride-ethanol-ammonia (0.88) 40/10/10

(H) Ether-cyclohexane 1/1

(I) Methanol-chloroform 5/95 (J) Ether

(K) Methylene chloride ether 1/1

(L) Methylene chloride-ethanol-ammonia (0.88) 75/8/1 (M) Isopropyl acetate (N) Ethyl acetate-ether 1/1

(O) Methylene chloride-ethanol-ammonia (0.88)

83.5 / 15 / 1.5 (P) Acetic acid-ethyl acetate 1/99 (Q) Ethyl acetate-cyclohexane 1/1 (R) Chloroform-methanol 50/1 (S) Chloroform-methanol 19 / 1

(T) Methylene chloride-ethanol-ammonia (0.88) 150/8/1 (U) Methylene chloride-ethanol-ammonia (0.88) 89/10/1 (V) Petroleum ether (eg 60- 80 ° C) - ethyl acetate 2/1 (W) Cyclohexane-ether 2/1.

The intermediates are subjected to a usual purity control by TLC, with detection in ultraviolet light and use of sprayed reagents such as potassium permanganate (KMn04). In addition, indole intermediates are detected by spraying aqueous ceric sulfate (CeIV) and tryptamines by spraying an iodoplatinic acid (AIP) or ceric sulfate solution.

The proton nuclear magnetic resonance (NMR) spectra ('H) are obtained either at 90 MHz using a Varian EM 390 device, or at 250 MHz using a Bruker AM or WM 250 device. S = singlet, d = doublet, t = triplet, q = quadruplet and m = multiplet.

Preparation 1

N-methyl-4-nìtrobenzene-ethanesulfonamide hydrate (411)

A solution of 6.5 g of 4-nitrobenzene-ethanesulfonyl chloride in 50 ml of methylene chloride is added dropwise over a period of 0.25 hours to a rapidly stirred ice-cold mixture of 4 ml of 40 mg aqueous methylamine % in 20 ml of methylene chloride. Additional 1 ml portions of 40% aqueous methylamine are added after stirring the suspension at 0 ° C for another hour and 0.5 hours respectively. The suspension was then stirred at 0 ° C for a further 0.5 hour before evaporating under reduced pressure to obtain a solid (about 7.0 g). This material is triturated with 100 ml of water and the solid is collected by filtration and then washed with 50 ml of petroleum ether (mp 60-80 ° C) and dried to obtain the title compound in the form of powder (5.45 g) mp 126-129 ° C.

Analysis for C9H12N204S • 0.25H2O:

Calculated: C = 43.45; H = 5.1; N = ll, 3%

Found: C = 43.35; H = 4.9; N = ll, l%

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Preparation 2

4-Amino-N-methylbenzene-ethanesulfonamide

A solution of 7.9 g of the product of preparation 1 in 150 ml of ethanol and 10 ml of dimethylformamide is added to a previously reduced suspension of 10% palladium oxide on carbon (1.0 g, aqueous paste at 50%) in 50 ml of ethanol and hydrogenated at atmospheric pressure. After 2.75 hours, a new portion (1.0 g) of catalyst is added and the hydrogenation is continued for a further 2 hours. A total of 2.141 of hydrogen is absorbed. The catalyst and the solvent are removed, respectively by filtration and by rotary evaporation, and the residual solid (8 g) is extracted with three 50 ml portions of boiling ethyl acetate. The combined hot extracts are filtered and evaporated to dryness under reduced pressure to obtain a solid. This material is triturated with petroleum ether (m.p. 60-80 ° C) to obtain the title compound in the form of a powder (5.2 g) m.p. 101-105 ° C.

Preparation 3

4-hydrazino-N-methylbenzene-ethanesulfonamide hydrochloride

1.0 g of the product of preparation 2 suspended in 6 ml of water is treated with 10 ml of concentrated hydrochloric acid, which precipitates the hydrochloride. The mixture is then cooled to -5 ° C and treated with 0.38 g of sodium nitrite in 2 ml of water and stirred for 50 minutes while keeping the temperature below -5DC. The suspension is quickly filtered to remove the unreacted starting material and the filtrate is slowly added to 5.0 g of stannous chloride in 10 ml of concentrated hydrochloric acid at - 5 ° C. The solution is allowed to warm up at 20 ° C with vigorous agitation, the precipitate formed is collected and washed with 50 ml of ether to obtain the title compound (1.2 g; purity 66%) in the form of a powder. CCM (A): Rf = 0.8 (AIP).

Preparation 4

4- [- (3-Cyanopropylidene Jhydrazino J-N-methyl-benzene-ethanesulfon-amide

To a filtered solution of 0.6 g of the product of preparation 3 (having a purity of 66%) in 13 ml of water and 0.25 ml of 2N dilute hydrochloric acid, 0.23 g of 3- cyanopropanal-dimethyl-acetal and the solution obtained is stirred at room temperature for 24 hours. The precipitated solid is filtered off, washed with two 30 ml portions of water and 50 ml of diethyl ether and then dried to obtain the title compound in the form of a powder (0.3 g) m.p. 96-97 ° C.

Preparation 5

3- (Cyanomethyl) -N-methyl-1H-indole-5-ethanesulfonamide

A suspension of 0.25 g of the product of preparation 4 in 2.5 g of polyphosphate ester and 5 ml of chloroform is heated at reflux for 5 minutes, then poured onto ice. The suspension obtained is stirred for 20 minutes and then extracted with four 10 ml portions of chloroform. The extracts are washed with 10 ml of 8% sodium bicarbonate and 10 ml of water, then dried, filtered and evaporated to give 0.35 g of an oil. This oil is chromatographed (J) to obtain the title compound (0.06 g) as an oil. TLC (J): Rf = 0.5 (U.V.).

Example 1

3- (2-aminoethyl) -N-methyl-1H-indole-5-ethanesul-fonamide hemisuccinate

Process (I)

A solution of 1.019 g of the product of preparation 3 in 25 ml of methanol and 5 ml of water is stirred at 50 ° C. and 0.117 g of 4-chlorobutanal-dimethylacetal is added. After 0.75 hours of stirring at 50 ° C, 0.117 g of 4-chlorobutanal-dimethylacetal is added and stirring is continued at 50 ° C for a further 0.75 hours. The pH of the solution is adjusted to 4 by the addition of 0.3 g of ammonium acetate and the mixture is brought to reflux for 5 hours. The solvent is removed by evaporation under reduced pressure and the residue is treated with 15 ml of a saturated aqueous potassium carbonate solution and extraction is carried out with four 50 ml portions of ethyl acetate. The extracts are dried (MgSO4) and concentrated in the form of a gum (0.69 g). This material is chromatographed (B), (C) to obtain the free base of tryptamine in the form of a gum (0.072 g) which is taken up in 2 ml of hot isopropanol and treated with a hot solution of 0.0151 g of succinic acid in 0.5 ml of hot isopropanol. After adding approximately 1.0 ml of absolute alcohol to the boiling mixture, the solution is allowed to cool. The solid which crystallizes is collected by filtration, washed with ethyl ether and dried to obtain the title compound in the form of a powder (0.046 g) m.p. 133-138 ° C.

Analysis for C13H19N302S • 0.5C4H604 • 0.1C3H80 • 0.75H20:

Calculated: C = 51.1; H = 6.8; N = 1I, 7%

Found: C = 50.8; H = 6.1; N = ll, 4%

NMR S (CD3SOCD3) 2.65 (3H, s, MeNHSO2) 2.7-3.4 (8H, m, NHSQ2CH2CH2 and CH2CH2NH2), 6.8-7.5 (4H, m, aromatic).

Example 2

N-methyl-3- [2- (methyl lamino) ethyl] -1 H-indole-5-ethanesulfonamide combined with succinic acid and water (6/4/3)

A solution of 0.45 g of the product of preparation 5 is hydrogenated in 25 ml of ethanolic methylamine (25% w / v) on 0.8 g of 10% palladium oxide on carbon (50% aqueous paste) previously reduced in 50 ml of ethanol. The catalyst is removed by filtration on "Hyflo" and the filtrate is concentrated to obtain 0.45 g of a gum which is dissolved in 5 ml of hot isopropanol and which is treated with a solution of 0.093 g of acid succinic in 0.5 ml of methanol. A thick gum precipitates. The reaction mixture is concentrated in vacuo (about 1 ml of solvent). The solvent is decanted and the residual gum is triturated with three 25 ml portions of diethyl ether to obtain a solid which is separated by filtration and dried to obtain the title compound in the form of a powder (0, 33 g) pf = 62-65 C.

Analysis for C14H21N302S • 0.66C4H602 • 0.5H20:

Calculated: C = 52.3; H = 7.2; N = 10.9%

Found: C = 52.5; H = 6.8; N = 11.0%

The NMR spectrum agrees with that of Example 3.

Example 3

N-methyl hydrochloride 1-3- [2- (methylamino) ethyl] -1 H-indole-5-ethanesulfonamide

In a similar manner to that of Example 2, 0.70 g of the product of Preparation 5 is hydrogenated, filtered and the filtrate is concentrated to obtain 0.7 g of a gum which is purified by chromatography flash (T, column diameter 3 cm). The gum obtained (0.3 g) is extracted with 20 ml of ethyl acetate, filtered and treated with an excess of hydrochloric acid in ether. The solid is collected by filtration, washed with 25 ml of ether and dried (15 h, 20 ° C, vacuum gun) to obtain the title compound in the form of a powder (0.24 g), m.p. 151-154 C.

Analysis for C14H21N302SHC10,5H20-0,07C4Hs02:

Calculated: C = 49.3; H = 6.8; N = 12.1%

Found: C = 49.3; H = 6.6; N = ll, 8%

NMR 8 (CD3SOCD3) 2.50 (3H, s NHMe) 2.66 (3H, s S02NHMe) 2.9-3.5 (8H, m CH2CHZSQ2NH and CH2CH2NH) and 6.9-7.5 (aromatic) .

Example 4

3- (2-Aminoethyl) -N- (phenylmethyl) -1H-indole-5-ethanesulfonamide combined with Creatinine, sulfuric acid and water (1/1/1/1)

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(1) 4-Nitro-N- (phenylmethyl) benzene-ethanesulfonamide.

9.83 ml of benzylamine in 10 ml of dichloromethane are added dropwise to a stirred ice-cold solution of 7 g of 4-nitrobenzene-ethanesulfonyl chloride in 250 ml of dichloromethane. After 18 hours, the reaction mixture is washed with three 40 ml portions of water and three 25 ml portions of salt water, dried (Na2SO4) and evaporated to dryness then the product is recrystallized from 50 ml of isopropanol to obtain the title compound as needles (6 g), mp 125-127 ° C.

(2) 4-Amino-N- (phenylmethyl) benzene-ethanesulfonamide.

A suspension of 11 g of the product from stage (1) is hydrogenated in 120 ml of methanol over 2 g of 10% palladium oxide on charcoal (50% aqueous paste) previously reduced at ordinary temperature and under pressure until that the fixation of hydrogen (1,991) ceases. The catalyst is filtered off and the filtrate is evaporated to dryness to obtain a solid which is purified by crystallization from methanol to obtain the title compound in the form of a solid (3.2 g) m.p. 109-111 ° C.

TLC (E): Rf = 0.4 (Ce, v).

(3) 4-hydrazino-N- (phenylmethyl) benzene-ethanesulfonamide hydrochloride.

A solution of 0.25 g of sodium nitrite in 1.9 ml of water is added to a cold suspension of 1 g of the product of stage (2) in a mixture of 7.5 ml of concentrated hydrochloric acid and 4 , 5 ml of water while keeping the temperature below - 5 ° C. This mixture is stirred at - 5 ° C for 50 minutes and the remaining solid is filtered off. The ice-cold filtrate is then added slowly to a solution of 3.5 g of stannous chloride dihydrate in 7.5 ml of concentrated hydrochloric acid while keeping the temperature below 0 ° C. After the addition, the mixture is stirred mixing at room temperature for 3 hours, collect the solid, wash with three 50 ml portions of diethyl ether and dry to obtain the title compound as a powder (0.46 g). TLC (B): Rf = 0.43 (AIP).

(4) 3- (2-Aminoethyl) -N- (phenylmethyl) -1H-indole-5-ethansulfon-amide combined with creatinine, sulfuric acid and water (1/1/1/1).

0.18 g of 4-chlorobutanal-dimethylacetal is added to a stirred solution of 0.45 g of the product of stage (3) in a mixture of 18 ml of ethanol and 4.5 ml of water and the mixture is heated at reflux for 2 hours. The cooled mixture is evaporated to dryness and the residue is chromatographed (A) twice to obtain tryptamine in the form of an oil (70 mg) which is dissolved in a boiling mixture of 5.6 ml of ethanol and 0 , 7 ml of water and which is treated with 0.1 ml of an aqueous solution of creatinine and sulfuric acid (1/1, 2M). Upon cooling, the title compound precipitates as a solid (96 mg) m.p. 217-220 ° C (softening at 210 ° C).

Analysis for C19H23N302S • C4H7N30 • H2S04 • H20:

Calculated: C = 47.1; H = 5.8; N = 14.3%

Found: C = 47.0; H = 5.9; N = 14.2%

NMR (CD3SOCD3) 2.9-3.3 (8H, m, NHS02CH2CH2 and CH2CH2NH2), 4.24 (2H, s, CH2NHS02), 6.85-7.5 (m, aromatic).

Example 5

3- [2-Ethylamino) ethyl hemihydrate hemisuccinate -N-methyl-1H-indole-5-ethanesulfonamide

Process (I)

A 10% suspension of palladium oxide on hydrogen (0.8 g of a 50% aqueous paste) is hydrogenated beforehand for 20 minutes in 5 ml of ethanol. 0.40 g of the product of preparation 5 is added to 25 ml of ethanolic ethylamine and the suspension obtained is stirred for 2 hours at 20 ° C. The suspension is filtered on Hyiio and the filtrate is concentrated in vacuo to obtain 0, 38 g of an oil which is chromatographed twice (B) to obtain

0.114 g of tryptamine in the form of an oil. The oil is dissolved in 2 ml of absolute ethanol and 22.5 mg of succinic acid in ethanol are added. The crystals are collected by filtration to obtain 70 mg of the title compound, m.p. 148-150 ° C.

Analysis for C] 5H23N302S • 0.5C4H604 • 0.5H20:

Calculated: C = 54.1; H = 7.2; N = ll, l%

Found: C = 54.5; H = 7.1; N = 10.9%

NMR (CD3SOCD3) 1.11 (3H, t, NHCH2Me), 2.64 (3H, s, MeNHS02), 2.78 (2H, q, NHCH2CH3), 2.85-3.4 (8H, m, NHS02CH2CH2 , and CH2CH2NH) 6.9-7.5 (4H, m, aromatic).

Process (II)

(1) N- [2- [5- [2 - [(methylamino) sulfonyl] ethyl] -1H-indole-3-yl] -ethyljacet amide.

A solution of 0.3 g of the product of Example 1 is treated in

15 ml of anhydrous tetrahydrofuran with 0.084 ml of acetic anhydride and the mixture is stirred at room temperature for 1.5 hours. Then the solution is evaporated to dryness twice and the residue is dissolved in 20 ml of ethyl acetate. This solution in ethyl acetate is washed with 20 ml of 8% aqueous sodium bicarbonate and then with 10 ml of water, dried and evaporated under reduced pressure to obtain 0.45 g of a gum. This material is chromatographed (A) to obtain the title compound as a gum (0.389 g) TLC (A): Rf = 0.6.

(2) 3- [2- (Ethylamino) ethyl] -N-methyl-1H-indole-5-ethanesulfonamide hemisuccinate.

A solution of 0.3 g of the product from stage (1) is added to

16 ml of anhydrous tetrahydrofuran (THF) to a stirred mixture of 0.353 g of lithium aluminum hydride in 20 ml of THF under a nitrogen atmosphere. The suspension obtained is stirred for

2 hours at reflux then allowed to stand overnight at room temperature before bringing to reflux for another hour. After cooling the reaction bath in an ice bath, 10 ml of water are added and the mixture obtained is filtered on Hyflo. The filtrate is extracted with four 25 ml portions of ethyl acetate and the extracts are dried (MgSO4) and then evaporated to give 0.187 g of a gum. This material is chromatographed (A) to obtain the free base as 0.12 g of a gum. A solution of 0.12 g of the free base in 2 ml of hot absolute alcohol is treated with a solution of 0.0229 g of succinic acid in 0.75 ml of methanol. The solution obtained is evaporated to dryness to obtain a foam which is triturated with anhydrous ether to obtain the title compound in the form of a hygroscopic foam (0.068 g), m.p. 65-75 ° C, which the NMR and the TLC (B; Rf = 0.25) reveal identical to the product of the process (I).

Example 6

3- (3-Aminopropyl) -N-methyl-1H-indole-5-ethanesulfonamide combined with oxalic acid and ethanol (111,210.83)

(1) 3- [3- (1,3-Dihydro-1,3-dioxo-2H-indole-2-yl) propyl] -N-meth-yl-1H-indole-5-ethanesulfonamide.

A mixture of 2.5 g of the product of preparation 3 (having a purity of 68%) and 3.15 g of 2- (5,5-dimethoxypentyl) -lH is stirred at room temperature for 1.75 hours -iso-indole-1.3 (2H) -dione (having a purity of 83%) in 200 ml of 10% aqueous acetic acid and then refluxed for 3.5 hours. The mixture is allowed to cool, extracted with three 100 ml portions of chloroform and the combined extracts are washed with 100 ml of 2N hydrochloric acid and 100 ml of 2N sodium carbonate, dried (Na2SO4) and concentrated in vacuo. By residual column gum (4.33 g), short column chromatography (F, column diameter: 15 cm), 0.43 g of a solid is obtained. By crystallization of this solid in 10 ml of a 1/1 mixture of chloroform and methanol, the title compound is obtained in the form of a solid (0.25 g), m.p. = 169-169.5 ° C. TLC (F): Rf = 0.19 (CeIV).

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(2) 3- (3-Aminopropyl) -N-methyl-1H-indole-5-ethanesulfon-amide combined with oxalic acid and ethanol (1 / 1.2 / 0.38).

0.34 ml of hydrazine hydrate is added to a reflux suspension of 250 mg of the product of stage (1) in 10 ml of ethanol, the solution obtained is stirred for 4 hours and then allowed to cool. The suspension is concentrated in vacuo and the residual solid is partitioned between 25 ml of 2N sodium carbonate and three 25 ml portions of ethyl acetate. The combined organic extracts are then dried (Na2SO4) and concentrated in vacuo. By flash column chromatography (G, column diameter: 1 cm) of the residue (110 mg), 98 mg of a gum are obtained, which is dissolved in 3 ml of absolute ethanol at reflux, and a solution of 30 is added. mg of oxalic acid in 0.5 ml of absolute ethanol. The gum suspension is gently heated to obtain a solution and allowed to cool with stirring. The suspension obtained is filtered and the solid is washed with three 1 ml portions of absolute ethanol and dried under vacuum at 50 ° C for 18 hours to obtain the title compound as a solid (118 mg), m.p. 160-162 ° C (softening at> 98 ° C).

Analysis for C14H21N302S- 1,2C2H204-0,83C2H <50:

Calculated: C = 49.1; H = 6.5; N = 9.5%

Found: C = 49.2; H = 6.85; N = 9.6%

NMR 8 (CD3SOCD3) 1.90 (2H, m, CH2CH2CH2NH2), 2.62 (3H, d, MeNHS02), 2.73 and 2.82 (4H, t and t, CH2CH2CH2NH2), 2.95-3, 3 (4H, m, NHSQ2CH2CH2), 6.95-7.45 (4H, m, aromatic).

Example 7

3- (2-Aminopropylj -N-methyl-1H-indole-5-ethane-sulfonamide hydrochloride

(1) 4-Nitropentanal.

To a cold solution of 45 ml of acrolein and 120 ml of nitroethane, in 750 ml of ether, a solution of 15 drops of tri-n-butylphosphine in 60 ml of ether is added without allowing the temperature to exceed - 8 ° C. The reaction is stirred for a further 30 minutes, 2 drops of methyl iodide are added and the ether is removed by evaporation under vacuum at 40 ° C. The residue is purified by column chromatography (H) to obtain 6.7 g of an oil which is distilled at 130-135 ° C (4 mbar) to obtain the title compound in the form of an oil (1.5 g). TLC (H): Rf - 0.3 (KMn04).

(2) N-methyl-4- [2- (4-nitropentylidene) hydrazino] benzene-ethanesulfonamide.

To a filtered solution of 3.678 g of the product of preparation 3 (having a purity of 67%) in 20 ml of water, 1.5 g of 4-nitropentanal is added dropwise and the reaction is monitored by TLC. The reaction mixture is extracted with 200 ml of chloroform, dried (MgSO4) and evaporated in vacuo to obtain 2.8 g of the title compound in the form of an oil which is used without further purification in the following stage . TLC (I): Rf = 0.4 (CeIV).

(3) N-methyl-3- (2-nitropropyl) -1H-indole-5-ethanesulfonamide.

A solution of 2.8 g of the product of stage (2), 28 g of polyphosphate ester and 50 ml of chloroform is heated at reflux for 5 minutes, then poured onto 100 g of ice. The suspension obtained is stirred for 30 minutes and extracted with three 100 ml portions of chloroform. The organic extract is washed with two 100 ml portions of an 8% solution of sodium bicarbonate and two 100 ml portions of water, dried (MgSO4), filtered and evaporated to obtain 5.2 g of an oil. The oil is purified by flash chromatography (J. column diameter: 8 cm) to obtain 0.47 g of the title compound as an oil. TLC (J): Rf = 0.8 (KMn04, AIP).

Analysis for C14H19N304S:

Calculated: C = 51.7; H = 5.9; N = 12.9%

Found: C = 51.5; H = 5.6; N = 12.7%

(4) 3- (2-Aminopropyl) -N-methyl-1H-indole-5-ethanesulfonamide hydrochloride.

A solution of 0.43 g of the product of stage (3) is hydrogenated

in 50 ml of ethanol on 0.4 g of 10% palladium oxide on previously reduced charcoal, for 75.5 hours at atmospheric pressure and at room temperature. The reaction mixture is filtered and evaporated under vacuum to obtain 0.27 g of an oil which is chromatographed (A, column diameter: 3 cm) to obtain the tryptamine in the form of an oil (0.23 g). A solution of the oil in 5 ml of ethanol is treated with hydrochloric acid in ether (pH 3), the salt is filtered off and dried to obtain the title compound as a solid (0.2 g), pf 211-212 ° C.

Analysis for C14H21N302S, HC1 0.18H20:

Calculated: C = 50.2; H = 6.7; N = 12.5%

Found: C = 50.4; H = 6.7; N = 12.2%

NMR (CD3S0CD3) 1.19 (3H, d, CH-CH3), 2.64 (3H, d, SQ2NHCH3), 2.75-3.5 (7H, m, CH2CH (Me) NH2 and CH2CH2S02NH), 7 -7.55 (5H, m, aromatic + NHS02).

Example 8

3- (2-Aminoethyl) -N, N-dimethyl-l H-indole-5-ethanesulfonamide combined with creatinine and sulfuric acid (ljljl)

(1) 2- (1 H-indole-5-yl) -N, N-dimethylethenesulfonamide.

A mixture of 7.7 g of 5-bromo-indole, 5.3 g of N, N-dimethylethene-sulfonamide, 15 ml of triethylamine, 5 ml of acetonitrile is heated at 100 ° C. in an autoclave for 3 hours. 0.35 g of palladium (II) acetate and 0.95 g of tri-o-tolylphosphine. The cooled mixture obtained is subjected to a partition between 300 ml of 2N hydrochloric acid and two 150 ml portions of ethyl acetate. The combined extracts are dried (Na2SO4) and evaporated in vacuo. The residue is purified by flash chromatography (V, 7 cm column) to obtain the title compound as a crystalline solid (3.8 g), m.p. 148-150 ° C.

(2) N, N-dimethyl-1 H-indole-5-ethanesulfonamide.

A solution of 3.8 g of the product of stage (1) in 400 ml of ethanol over 0.5 g of 10% palladium oxide on carbon (50% aqueous paste) is hydrogenated at ordinary temperature and pressure. %) during 2 hours. The catalyst is filtered off and replaced with a fresh quantity (0.5 g; 50% aqueous paste) and the hydrogenation is continued for one hour. The catalyst is filtered off and the filtrate is evaporated in vacuo to obtain 2.8 g of a solid which is recrystallized from a mixture of ethyl acetate and hexane to obtain the title compound in the form of a solid (2.0 g), pf 125-127 ° C.

(3) 3 - [(Dimethylamino) methyl] -N, N-dimethyl-1 H-indole-5-etha-nesulfonamide.

A solution of 0.8 g of the product of stage (2) in 40 ml of acetonitrile containing 0.6 g of N, N-dimethylmethyleneammonium chloride is stirred at room temperature for 2 hours. The solution obtained is subjected to a partition between 50 ml of 2N sodium carbonate and two 50 ml portions of ethyl acetate. The organic extracts are dried (Na2SO4) and evaporated in vacuo to obtain a solid. By trituration with ether, the title compound is obtained in the form of a solid (0.9 g), m.p. 156-159th C.

(4) 3- (Cyanomethyl) -N, N-dimethyl-1 H-indole-5-ethanesulfon-amide.

1.1 ml of iodomethane are added to a stirred solution of 2.7 g of the product of stage (3) in 30 ml of anhydrous dimethylsulfoxide and the solution obtained is stirred at room temperature for 10 minutes. 2.7 g of potassium cyanide are added and the mixture obtained is stirred at room temperature overnight. The mixture is partitioned between 300 ml of 2N sodium carbonate and two 100 ml portions of ethyl acetate. We dry

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the combined extracts (Na2SO4) and evaporated in vacuo to obtain an oil which is chromatographed by flash chromatography (J, 5 cm column) to obtain the title compound as a solid (1.3 g), m.p. 105-107 ° C.

(5) 3- (2-Aminoethyl) -N, N-dimethyl-1H-indole-5-ethanesulfon-amide combined with creatinine and sulfuric acid (1/1/1).

A solution of 0.2 g of the product of stage (4) in 40 ml of ethanol containing 0.1 ml of concentrated hydrochloric acid, 0.2 g of palladium oxide is hydrogenated at ordinary temperature and pressure. at 10% on charcoal (50% aqueous paste) for 24 hours. The catalyst is filtered off and the filtrate is evaporated in vacuo to obtain an oil. The oil is subjected to a partition between 20 ml of 2N hydrochloric acid and 20 ml of ethyl acetate. The aqueous layer is alkalinized (Na2CO3) and extracted with two 20 ml portions of ethyl acetate. The combined extracts are dried (Na2SO4) and evaporated in vacuo to obtain tryptamine in the form of 0.05 g of an oil which is dissolved in a hot mixture of 9 ml of ethanol and 1 ml of water and 0.08 ml of a 1/1 solution of creatinine in sulfuric acid (2M) is added. By filtration of the cooled mixture, the title compound is obtained in the form of a solid (0.05 g), m.p. 223-225 ° C (decomposition).

Analysis for C14H21N302S • C4H7N30 • H2S03 • 2H20:

Calculated: C = 39.9; H = 6.3; N = 15.5%

Found: C = 39.9; H = 6.2; N = 15.85%

NMR 8 (CD3S0CD3) 2.82 (6H, s, S02NMe2), 2.9-3.4 (8H, m, CH2S02N and CH2CH2NH2), 7.0-7.55 (4H, m, aromatic).

Example 9

3- [2- (Dimethylamino) ethyl] -N-methyl-1H-indole-5-ethanesulfon-amide combined with creatinine, sulfuric acid and water (1/2 / 1.512)

A solution of 0.4 g of the product of preparation 5 in 25 ml of ethanolic dimethylamine (33% w / w) is hydrogenated at ordinary temperature and pressure over 0.7 g of 10% palladium oxide. % on charcoal (50% aqueous paste) previously reduced, for 3 hours. The catalyst is filtered off and the filtrate is concentrated in vacuo to give 0.35 g of an oil which is purified by flash chromatography (B, column diameter: 8 cm). The oil obtained (0.25 g) is dissolved in 20 ml of hot ethanol and 2.5 ml of water and treated with 0.4 ml of a 1/1 aqueous solution of creatinine and sulfuric acid (2M) and cooled to 5 ° C to precipitate the title compound as a solid (0.22 g), mp 193-197 ° C.

Analysis for Cx 5H23N302S • 2C4H-, N30 • 1,5H2S04 • 2H20:

Calculated: C = 38.45; H = 6.05; N = 17.5%

Found: C = 38.2; H = 5.6; N = 17.0%

The NMR characteristics agree with those of Example 10.

Example 10

3- [2- (dimethylamino) ethyl] -N-methyl-1 H-indole-5-ethanesulfonamide hydrochloride

Process (I)

A suspension of 14 g of 10% palladium oxide on carbon (50% paste with water) in 100 ml of ethanol is hydrogenated beforehand for 20 minutes. 8 g of the product of preparation 5 are added in 400 ml of ethanolic dimethylamine (33% w / v) and the suspension obtained is stirred for 18 hours at 20 ° C. under a hydrogen atmosphere. The suspension is filtered through Hyflo and evaporated to obtain 8.4 g of an oil which is purified by flash chromatography (column diameter: 8 cm) to obtain tryptamine in the form of an oil (6.0 g ). The oil is extracted with 2 liters of diethyl ether and 200 ml of ethyl acetate to leave 0.5 g of a residue which is discarded. The organic extracts are combined, evaporated in vacuo and dissolved in 300 ml of Analar ethyl acetate. Hydrochloric acid in ether is added dropwise with rapid stirring. The crystals obtained are collected by filtration, washed with 100 ml of ether and dried at 60 ° C for 16 hours to obtain 5.5 g of the title compound m.p. 137-139 ° C.

Analysis for C15H23N302S-HC1:

Calculated: C = 52.1; H = 7.0; N = 12.15%

Found: C = 51.8; H = 6.7; N = ll, 9%

NMR (CD3SOCD3) 2.65 (3H, d, MeNHSQ2), 2.84 (6H, s, NMe2), 3.0-3.45 (8H, m, CH2CH2NMe2 and NHSQ2CH2CH2), 7.0-7.6 (5H, m, aromatic + NHS02).

Process (II)

(1) 5- [2 - [(methylamino) sulfonyl] ethyl] -1H-indole-3-acetic acid.

A solution of 0.3 g of the product of preparation 5 in 15 ml of ethanol and 15 ml of water containing 1.5 g of potassium hydroxide is heated at reflux for 18 hours, the mixture is cooled and the mixture is evaporated. ethanol under vacuum. The residue is partitioned between 50 ml of 2N hydrochloric acid and two 50 ml portions of ethyl acetate. The combined extracts are dried (Na2SO4) and evaporated in vacuo, The residue is purified by "flash" chromatography (M, column 3 cm in diameter) to obtain the title compound as an oil which crystallizes on standing ( 0.1 g), pf 123-125 ° C.

(2) 3- (2-Hydroxyethyl) -N-methyl-1H-indole-5-ethanesulfon-amide.

A solution of 1.0 g of the product of stage (1) in 60 ml of anhydrous tetrahydrofuran (THF) containing 1.0 g of lithium aluminum hydride is heated at reflux under nitrogen for 6 hours. The mixture obtained is cooled and the excess reducing agent is decomposed by adding an excess of 10% aqueous THF. The mixture obtained is partitioned between 50 ml of 2N sodium carbonate and two 50 ml portions of ethyl acetate. The combined extracts are dried (Na2SO4) and evaporated in vacuo to obtain an oil which is purified by "flash" chromatography (N, column diameter: 4 cm) to obtain the title compound as an oil ( 0.35 g).

TLC (N): Rf = 0.4 (CeIV).

(3) 3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-ethanesulfonamide hydrochloride.

A solution of 0.44 g of triphé-nylphosphine in 3 ml of tetrahydrofuran (THF) is added in a single portion to a solution of 0.3 g of N-bromosuccinimide (NBS) in 5 ml of THF to obtain a precipitate. A solution of 0.39 g of the product of stage (2) in 10 ml of THF is added and the mixture is stirred at room temperature for 18 hours. 20 ml of a solution of dimethylamine in ethanol (33% w / v) are added and the solution obtained is stirred at room temperature for 3 days then evaporated in vacuo and the residue is partitioned between 25 ml 2N hydrochloric acid and two 25 ml portions of ethyl acetate. The aqueous layer is made alkaline (Na2CO3) and extracted with two 25 ml portions of ethyl acetate. The combined extracts are dried (Na2SO4) and evaporated in vacuo to obtain an oil which is purified by "flash" chromatography (A, column diameter: 4 cm) to obtain 0.08 g of the pure free base in the form of an oil. This oil is dissolved in 5 ml of absolute ethanol acidified with hydrochloric acid in ether and diluted with anhydrous ether to precipitate the title compound in the form of a hygroscopic solid which is revealed by NMR and TLC (A, Rf = 0.4) to be identical to the product of process (I).

Process (III)

(1) 4- [2- [4- (Dimethylamino) butylidene] hydrazino] -N-methylben-zene-ethanesulfonamide.

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0.87 g of 4,4-dimethoxy-N, N-dimethylbutanamine is added to a solution of 2.0 g of the product of preparation 3 (having a purity of approximately 65%) in 40 ml of water, 2.2 ml of 2N hydrochloric acid is added and the mixture is stirred (pH ~ 1.5) at ordinary temperature under nitrogen for 4 hours. 160 mg of acetal are added and stirring is continued at room temperature for one hour. The mixture is made alkaline with 20 ml of an 8% aqueous solution of sodium bicarbonate and extracted with three 70 ml portions of chloroform; the aqueous layer is saturated with sodium chloride and extracted again with three 120 ml portions of chloroform. The combined organic layers are dried (MgSO 4) and evaporated to give 2.25 g of an oil. A 133 mg sample of the oil is purified by flash chromatography (U, column diameter: 2 cm) to obtain the title compound as an oil (71 mg).

CCM (U): Rf = 0.4 (AIP).

(2) 3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-ethanesulfonamide hydrochloride.

2.1 g of the product from stage (1) is refluxed with 10.5 g of polyphosphate ester in 40 ml of chloroform with stirring under nitrogen for 8 minutes. The mixture is poured onto ice, stirred for 1.75 hours, basified with 100 ml of 2N sodium carbonate and extracted with three 250 ml portions of chloroform. The organic layers are dried (MgSO 4) and evaporated to obtain 1.96 g of an oil. By partial purification by flash chromatography (O, column diameter: 3 cm), 0.726 g of an oil is obtained; further purification by short column chromatography provides the pure free base also as an oil (0.56 g). The oil is chaulfated with 30 ml of Analar ethyl acetate and a portion (12 ml) of the solution is filtered which is acidified with hydrochloric acid in ether (to pH 2). The precipitate is washed by decantation with anhydrous ether and dried under vacuum (60 ° C., 17 hours) to obtain the title compound in the form of a hygroscopic solid (129 mg) which is revealed by NMR and TLC ( O, Rf = 0.25) be identical to the product of the process®.

Process (IV)

(1) N, N-dimethyl-5- [2 - [(methylamino) sulfonyl] ethyl] -1H-indole-3-acetamide.

A mixture of 0.57 g of N, N'-carbonyl-diimidazole and 0.9 g of the product from stage (1) of process (II) in 25 ml of freshly distilled tetrahydrofuran is stirred at room temperature for 1 hour. The mixture is then cooled to 0 ° C and 2 ml of dimethylamine are added. After stirring (at 0 ° C) for 2 hours, the solvent is removed under reduced pressure. The residue (P) is chromatographed to obtain the title compound as an oil (0.53 g).

TLC (P): Rf = 0.25 (CeIV).

(2) 2- [2- (Dimethylaminô) ethyl] -N-methyl-1H-indole-5-ethanesulfonamide hydrochloride.

A solution of 0.15 g of the product of stage (1) in 5 ml of freshly distilled tetrahydrofuran is added to a cold suspension (0 ° C) of 87 mg of lithium aluminum hydride in 10 ml of freshly tetrahydrofuran distilled under nitrogen and the mixture is heated to reflux for 2 hours. The cooled mixture is added to 15 ml of a saturated potassium carbonate solution and the organic phase is separated. The aqueous phase is extracted with 20 ml of ethanol and the combined organic phases are evaporated under reduced pressure to obtain an oil which is dissolved in 1 ml of absolute alcohol and 3 ml of a hydrochloric acid solution are added in ether. The solvent is removed by evaporation under reduced pressure and the residue is triturated with a 1/1 mixture of ethyl acetate and cyclohexane to obtain the title compound (0.1 g), m.p. 132-134 ° C, which is revealed by TLC (B, Rf = 0.1) and NMR to be identical to the product of process (I).

Process (V)

(1) (E) -2- (1H-indole-5-yl) -N-methylethenesulfonamide.

Heated at 100 ° C in an autoclave for 3 hours a mixture of 6.6 g of 5-bromo-indole, 5.1 g of N-methylethenesulfon-amide, 75 mg of palladium (II) acetate, 0, 2 g of tri-o-tolylphos-phine, 12 ml of triethylamine and 5 ml of acetonitrile. The reaction mixture is cooled and partitioned between 300 ml IN hydrochloric acid and two 150 ml portions of ethyl acetate. The combined extracts are dried (Na2SO4) and evaporated in vacuo to obtain an oil which is purified by "flash" chromatography (Q, column diameter: 7 cm) to obtain the title compound as a solid ( 2.3 g), pf 164-166 C.

TLC (Q): Rf = 0.25 (Ce, v).

(2) N-methyl-1 H-indole-5-ethanesulfonamide.

A solution of 2.3 g of the product of stage (1) in a mixture of 30 ml of ethyl acetate and 15 ml of methanol over 0.2 g of hydrogen oxide is hydrogenated at ordinary temperature and at ordinary pressure. 10% palladium on charcoal (50% aqueous paste) for 4 hours until the hydrogen fixation (240 ml) ceases. The catalyst is filtered off and the filtrate is evaporated in vacuo to obtain an oil which is crystallized from ethyl acetate to obtain the title compound as a solid (1.8 g), m.p. 122-124 "C.

TLC (R): Rf = 0.4 (Celv).

(3) N, N-dimethyl-5- [2 - [(methylamino) sulfonyl] ethyl] -oxo-1H-indole-3-acetamide.

0.3 ml of oxalyl chloride is added dropwise under nitrogen to a stirred solution of 0.7 g of the product of stage (2) in 30 ml of tetrahydrofuran and the solution obtained is stirred at ordinary temperature for one hour . Dimethylamine gas is then bubbled through the solution for 10 minutes. The suspension obtained is subjected to a partition between 50 ml of 2N hydrochloric acid and two 50 ml portions of ethyl acetate. The combined extracts are dried (Na2SO4) and evaporated in vacuo to obtain an oil which is purified by "flash" chromatography (S, column diameter: 4 cm). The oil obtained is crystallized from a mixture of ethyl acetate and hexane to obtain 0.4 g of the title compound in the form of a solid, m.p. 151-153; vs.

(4) 3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-ethanesulfonamide hydrochloride hemihydrate.

A solution of 0.3 g of the product of stage (3) in 30 ml of tetrahydrofuran containing 0.3 g of lithium aluminum hydride is heated at reflux for 3 hours, cooled and the excess d decomposed. reducing agent by addition of 10% aqueous THF. The mixture obtained is subjected to a partition between 100 ml of sodium carbonate (2N) and two 50 ml portions of ethyl acetate. The combined extracts are dried (Na2SO4) and evaporated in vacuo to obtain an oil which is purified by "flash" chromatography (A, column diameter: 4 cm). The oil obtained (0.15 g) is dissolved in 5 ml of absolute ethanol, acidified with hydrochloric acid in ether and the salt is precipitated by adding an excess of anhydrous ether. The salt is separated by filtration and dried in vacuo to obtain the title compound as a solid (0.12 g), m.p. 86-92 ° C (softening at 62 ° C) which is revealed by NMR and TLC (A, Rd = 0.4) to be identical to the product of the process (I).

Process (VI)

A solution of 0.4 g of the product of Example 1 in the form of the free base in 16 ml of n-propanol, cooled in an ice bath, is treated with 0.64 ml of aqueous formaldehyde (~ 40% solution) and the suspension obtained is stirred for 0.75 hours under a nitrogen atmosphere. 0.54 g of sodium borohydride is added and the mixture obtained is stirred in an ice bath for 2 hours. The suspension is treated with about 6 ml of 2N hydrochloric acid and stirred for 10 minutes. The mixture obtained is evaporated to a small volume (keeping the temperature below 50 ° C.), it is made alkaline with

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20 ml of an 8% aqueous solution of sodium bicarbonate and extracted with five 5 ml portions of ethyl acetate. The combined extracts are dried (MgSO4) and evaporated to give 0.35 g of an oil which is chromatographed (B) to obtain tryptamine in the form of an oil (0.48 g). One part (0.140 g) of the oil is treated in 2 ml of absolute ethanol with an excess (4 ml) of hydrochloric acid in ether and the mixture is evaporated to dryness to leave a semi-solid which is triturated with anhydrous ether to obtain the title compound as a solid (0.1 g), mp 130-136 ° C (softening at 128 ° C) which is revealed by NMR and TLC (A, Rf = 0.3) to be identical to the product of the process (I).

Process (VII)

To a solution of 146 mg of the product of Example 12 in 15 ml of anhydrous tetrahydrofuran at room temperature, 0.99 ml of a 1.0M solution of tetrabutylammonium fluoride in THF is added. After stirring at room temperature for a period of 40 min, 100 (of propylene oxide and then

1 ml of a 0.25M solution of methyl iodide in THF and the mixture is kept for 40 minutes at room temperature then the reaction is stopped with 20 ml of a 10% aqueous solution of sodium thiosulfate and extracted with two 15 ml portions of ethyl acetate. The organic extracts are dried (Na2SO4) and concentrated in vacuo. TLC analysis (D) of the reaction mixture indicates the presence of the title compound (Rf = 0.50) which is identical to a sample prepared according to the method (I).

Example 11

3- [2- (dimethylamino) ethyl] -N-methyl-1H-indole-5-etha-nesulfonamide oxalate

A hot solution of 0.13 g of the product of Example 10 is treated in the form of the free base with 40 mg of oxalic acid in

2 ml of ethanol and the oxalate precipitates immediately. The solvent is evaporated off and the residual solid is crystallized from 10 ml of hot methanol to obtain the title compound in the form of a solid (80 mg), m.p. 198-199 ° C.

Analysis for CisH23N302S • C2H204:

Calculated: C = 51.1; H = 6.3; N = 10.5%

Found: C = 50.9; H = 6.2; N = 10.4%

TLC: (L) Rf = 0.2 (AIP, Ce).

Example 12

3- [2- (dimethylamino) ethyl] -1H-indole-5-ethanesulfon-amide oxalate

Heated in an autoclave at 110 ° C for 3 hours, then at 175 ° C for a further 2 hours, a mixture of 70 mg of the product of stage (5) of Example 18 in 15 ml of liquid ammonia. By cooling to room temperature, the ammonia is allowed to evaporate and the autoclave is recharged with 2 ml of pyridine and 15 ml of liquid ammonia. After 14 hours at 155 ° C, the autoclave is cooled to room temperature and the ammonia is allowed to evaporate. The mixture is concentrated in vacuo and the gum obtained is purified by "flash" chromatography to give the product in the form of 15.3 mg of a vitreous material which is taken up in 0.25 ml of ethanol, filtered and is added to a solution of 4.6 mg of oxalic acid in 0.5 ml of ethanol. By concentration under vacuum, a solid is deposited, it is separated by filtration, washed with ether and dried under vacuum overnight to obtain 5 mg of the title compound.

CCM (A): (Rf = 0.25 (AIP, KMn04).

NMR 5 (CD3SOCD3) 2.83 (6H, s, NMe2), 3.0-3.4 (9H, m, CH2CH2NMe2 and CH2CH2SO2), 6.92 (2H, broad, S02NH2), 7.0-7, 6 (4H, m, aromatic).

Example 13

3- [2- (Dimethylamino) ethyl] -1H-indole-5-ethanesulfonamide (1) (E) -2- [3- (cyanomethyl) -1H-indole-5-yl] ethenesulfonamide.

A solution of 428 mg of ethenesulfonamide, 940 mg of 5-bromo-3- (cyanomethyl) -1H-indole, 21 mg of palladium (II) acetate is treated in an autoclave at 130 ° C. for 48 hours. , 67 mg of tri-o-tolylphosphine and 1.1 ml of anhydrous triethylamine in 15 ml of anhydrous acetonitrile. After cooling to room temperature, the mixture is poured into 30 ml of water and extracted with three 30 ml portions of ethyl acetate. The combined organic extracts are dried (MgSO4) and concentrated in vacuo. By "flash" chromatography (B) of the residue, a powder is obtained. By recrystallization, o (hexane-dichloromethane), 550 mg of the title compound are obtained in the form of a powder, m.p. 176-178 ° C.

(2) 3- (Cyanomethyl) -1 H-indole-5-ethanesulfonamide.

Hydrogenated, at ordinary temperature and pressure, a solution of 443.6 mg of the product of stage (1) in 50 ml of absolute ethanol on 1.30 g of 10% palladium oxide on carbon (paste aqueous 50%) in 30 ml of absolute ethanol which has been previously reduced, for a period of 18 hours. The catalyst is separated by filtration on a pad of sand and celite, then washed carefully with 200 ml of ethanol. The combined filtrates are concentrated in vacuo and the residue is purified by flash chromatography (B) to obtain a viscous oil which is solidified by trituration with diethyl ether to obtain the title compound in the form of an amorphous powder ( 260 mg), pf 109-111 ° C.

(3) 3- [2- (Dimethylamino) ethyl] -1H-indole-5-ethanesulfonamide.

A solution of 4.9 mg of the product of stage (2) in 5 ml of 33% ethanolic dimethylamine amine on 10 mg of 10% palladium oxide on carbon is hydrogenated at ordinary temperature and pressure. 50% aqueous paste) previously reduced in 5 ml of absolute ethanol for 14 hours. The mixture is filtered on a pad of sand-celite and then washed with three 10 ml portions of ethanol and the combined filtrates are concentrated in vacuo. By flash chromatography (A) of the residue, 3.7 mg of the title compound are obtained, which is revealed by TLC (A, Rf = 0.22) and NMR to be identical to the product of Example 12.

Example 14

3- [2- (ethylmethylamino) ethyl] -N-methyl-1H-indole-40 5-ethanesulfonamide hydrochloride

(1) N-ethylmethyl-5- [2 - [(methylamino) sulfonyl] ethyl] -1 H-indole-3-acetamide.

A solution of 0.7 g of the product from stage (1) of (II) of Example 10 in 50 ml of anhydrous tetrahydrofuran (THF) containing 0.5 g of is stirred at room temperature for one hour. car-bonyldiimidazole. 2 ml of N-methylamine are added and the solution is stirred at room temperature for 3 hours. The solution is subjected to a partition between 50 ml of 2N hydrochloric acid and two 50 portions of 50 ml of ethyl acetate. The combined extracts are washed with 50 ml of 2N sodium carbonate, dried over Na2SO4 and evaporated in vacuo to obtain an oil. The oil is purified by "flash" chromatography eluting with ethyl acetate to obtain the title compound as an oil (0.2 g). 55 TLC: ethyl acetate, (CeIV): Rf = 0.2.

(2) 3- [2- (ethylmethylamino) ethyl] -N-methyl-1 H-indole-5-ethanesulfonamide hydrochloride.

A solution of 0.2 g of the product of stage (1) in 50 ml of anhydrous THF containing 0.2 g of lithium aluminum hydride is heated under reflux for 24 hours, the mixture is cooled and the excess of reducing agent by addition of 10% aqueous THF. The mixture obtained is partitioned between 50 ml of 2N sodium carbonate and two 50 ml portions of ethyl acetate. The 65 combined extracts are dried. (Na2SO4) and evaporated in vacuo to obtain an oil which is dissolved in 5 ml of ethanol, acidified with hydrochloric acid in ether and the salt is precipitated by adding an excess (200 ml ) anhydrous ether. The salt is separated by filtration and

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dried in vacuo to obtain the title compound as a hygroscopic solid (0.08 g), m.p. 95-99 ° C.

Analysis for ClsH25N302S - HCl:

Calculated: C = 53.4; H = 7.3; N = ll, 7%

Found: C = 53.0; H = 7.6; N = ll, 4%

NMR 5 (CD3SOCD3) 1.28 (3H, t, CH2CH3), 2.65 (3H, d, S02NHCH3), 2.81 (3H, s, CH2NCH3), 3.0-3.5 (m, CH2CH2S02 and CH2CH2NMe and NCH2CH3), 7.0-7.6 (5H, m, aromatic + SO2NH).

Example 15

N-methyl-3 [2- (2-propenylamino) ethylJ-1H-indole-5-etha-nesulfonamide oxalate

(1) 5- [2 - [(Methylamino) sulfonyl] ethyl] -N- (2-propenyl) -1 H-indo-le-3-acetamide.

A solution of 0.7 g of the product from stage (1) of (II) of Example 10 in 50 ml of anhydrous tetrahydrofuran (THF) containing 0.5 g of caryldiimidazole is stirred at ordinary temperature for one hour. . 2 ml of allylamine are added and the solution is stirred at room temperature for 3 hours. The solution is partitioned between 50 ml of 2N hydrochloric acid and two 50 ml portions of ethyl acetate. The combined extracts are dried (Na2SO4) and evaporated in vacuo to obtain an oil. The oil is purified by "flash" chromatography eluting with ethyl acetate to obtain the title compound as an oil (0.25 g) which crystallizes on standing, m.p. 123-125 ° C.

(2) N-methyl-3- [2- (2-propenylamino) ethyl] -1H-indo-le-5-ethanesulfonamide oxalate.

A solution of 0.2 g of the product of stage (1) in 50 ml of anhydrous THF containing 0.4 g of lithium aluminum hydride is heated at reflux for 24 hours and the excess agent is destroyed reducing agent by addition of 10% aqueous THF. The mixture obtained is subjected to a partition between 50 ml of 5N hydrochloric acid and 30 ml of ethyl acetate. The aqueous layer is made alkaline (Na2CO3) and extracted with two 50 ml portions of ethyl acetate. The combined extracts are dried (Na2SO4) and evaporated in vacuo to obtain 82 mg of an oil which is dissolved in 5 ml of ethanol, acidified with a solution of 25 mg of oxalic acid in 2 ml of methanol and the solution is evaporated in vacuo. By trituration with anhydrous ether, the title compound is obtained in the form of a solid (80 mg), m.p. 105-108 ° C.

Analysis for C16H23N302S-C2H204- 1.5H20:

Calculated: C = 49.3; H = 6.4; N = 9.6%

Found: C = 49.7; H = 6.2; N = 9.6%

NMR (free base) 5 (CD3SOCD3) 2.65 (3H, s, S02NHMe), 3.0-3.4 (10H, m, CH2CH2S02 and CH2CH2N and NCH2CH =), 5.17 (2H, m, -CH = CH2), 5.88 (1H, m, -CH = CH2), 7.0-7.5 (4H, m, aromatic).

Example 16

N-methyl-3- [2- [(phenylmethylidene) amino] ethyl] -1H-indole-5-etha-nesulfonamide

Stirred under nitrogen at reflux for 2 hours, then at room temperature for 48 hours, a solution of 1.0 g of the free base of the product of Example 1 in 10 ml of absolute ethanol containing 0.04 g of freshly distilled benzaldehyde and 0.5 g of 3 Å molecular sieve. The suspension is filtered on "Hyflo" and the filtrate is evaporated under reduced pressure to obtain 0.036 g of a gum. By trituration with anhydrous ether, the title compound is obtained in the form of a powder (0.01 g), m.p. 146-148 ° C.

NMR 5 (CD3S0CD3 / CDC13) 2.72 (3H, d, S02NHMe) 3.08-3.32 (6H, m, CH2CH2S02 and CH2CH2N =), 6.3 (1H, q wide, S02NH) 7.38- 7.7 (6H, m, N = CH-Ph and indole-4) 8.18 (1H, s, N = CH).

Example 17

3- [2- (Dimethylamino) ethyl] -N- (2-propeny l) - 1H-indole-5-ethanesul-fonamide

A solution of 30 mg of the product from stage (5) of Example 18 and 2 ml of allylamine in anhydrous pyridine is heated at 100 ° C. in a “Reactivial” for 36 hours. The cooled reaction mixture is concentrated in vacuo and purified by "flash" chromatography (A) to obtain the title compound as a viscous oil (3.4 mg).

1 CCM (1): Rf = 0.36 (AIP).

NMR (CD3SOCD3) 2.26 (6H, s, NMe2) 3.68 (2H, broad t, CH2CH = CH2) 5.17 (1H, dd, CH = CH2, proton E), 5.32 (1H, dd , CH = CH2, proton Z) 5.9 (1H, ddt, CH = CH2), 7.4 (2H, broad, SO2NH and indole-4).

15 2 '

Example 18

3-f 2- (Dimethylamino) ethyl] -N-methyl-1H-indole-5-ethanesulfon-amide

(1) Phenyl 4-nitrobenzene ethanesulfonate.

To a solution of 14.4 g of 4-nitrobenzene-ethane-sulfonyl chloride in 200 ml of benzene and 5 ml of tetrahydrofuran (THF), 5.5 g of phenol and 8.5 ml of triethylamine are added in 20 ml of THF by cooling with ice and the suspension obtained is stirred at room temperature for one hour. The mixture obtained is washed with two 20 ml portions of dilute hydrochloric acid, dried (MgSO 4) and concentrated in an oil which solidifies on standing. The solid is washed with 400 ml of ether and air dried for one hour to obtain 11.45 g of phenyl sulfonate. A sample (400 mg) is recrystallized from 20 ml of ethanol to obtain the title compound in the form of a solid (250 mg) m.p. 90-91 ° C.

(2) Phenyl 4-aminobenzene ethanesulfonate hydrochloride.

A suspension of 11% is added to 2 g of 10% palladium oxide on charcoal (in the form of a 50% paste in water) in 50 ml of ethanol, which has been reduced beforehand. g of the product from stage (1) in 100 ml of ethanol and 200 ml of ethyl acetate and hydrogenation is carried out at atmospheric pressure and temperature for 2 hours. The hydrogen fixation is 1.9 liters. The catalyst is filtered off (Hyflo), washed with an additional 250 ml of ethanol, the solvent is evaporated and the residual oil is dissolved in 200 ml of chloroform. Hydrochloric acid in ethanol is added to the solution (at pH 1) and the title compound precipitates as a solid (3.1 g).

TLC, methylene chloride, Rf = 0.25 (Celv).

(3) Phenyl 4-hydrazinobenzene ethanesulfonate hydrochloride.

To a suspension of 1 g of the product of stage (2) in 10 ml of concentrated hydrochloric acid and 10 ml of water, 0.46 g of sodium nitrite is added in 2 ml of water at -53 ° C. salted iced). 20 ml of water are added, the suspension obtained is filtered and the filtrate is added to a solution of 6.6 g of stannous chloride in 10 ml of concentrated hydrochloric acid at - 5 = C. The mixture is stirred with room temperature for 16 hours. The solid obtained is filtered off, washed with 50 ml of ether and air-dried for 30 minutes to obtain the title compound (0.51 g) contaminated with a mineral material. It is used in the next stage without further purification.

TLC (A): Rf = 0.75.

(4) 4- [2- [4-Dimethylamino) butylidene] hydrazino] benzene-etha-65 phenyl nesulfonate.

A suspension of 0.5 g of the product from stage (3) and 0.5 g of 4,4-dimethoxy-N, N-dimethylbutanamine in 10 ml of water and 5 ml of is stirred at room temperature for 2 hours. 'chlorhy acid-

663 411

16

2N dric (pH 1). The solution obtained is saturated with potassium carbonate and extracted with four 20 ml portions of ethyl acetate. The extract is dried and evaporated to obtain the title compound as an oil (0.33 g) which is used in the next stage without further purification.

CCM (A): Rf = 0.5 (CeIV, AIP).

(5) 3- [2- (Dimethylamino) ethyl] -1 H -indole-5-phenyl ethanesulfonate.

0.33 g of the product from stage (4) is refluxed for 10 minutes in 3.3 g of polyphosphate ester and 8 ml of chloroform, poured onto 20 g of ice and neutralized with potassium carbonate solid. The aqueous layer is extracted with four 15 ml portions of chloroform, the extracts are combined, washed with 10 ml of salt water, dried and evaporated. The residue (B) is chromatographed to give the slightly impure product as 0.1 g of an oil. A small sample (15 mg) was repurified by preparative layer chromatography (L, 20 x 20 cm; 2 mm) to obtain the pure title compound as an oil (7 mg).

CCM (A): Rf = 0.5 (CeIV, AIP).

(6) 3- [2- (Dimethylamino) ethyl] -N-methyl-1 H-indole-5-ethane-sulfonamide.

70 mg of the product of stage (5) are heated in 4 ml of a solution of pyridine saturated with methylamine in a "Reactivial" for 1.5 hours. The mixture is concentrated and the residual oil is purified by column chromatography (B), to give the title compound as an oil (7 mg) which is revealed by NMR and TLC (B, Rf = 0.3 ) be identical to the product of process (I) of Example 10.

The following examples illustrate pharmaceutical compositions according to the invention containing 3- [2- (dimethyl-amino) ethyl] -N-methyl-1H-indole-5-ethanesulfonamide hydrochloride as active ingredient. Other compounds of the invention can be presented very similarly.

Tablets for oral administration

They can be prepared by conventional methods such as direct compression or wet granulation.

A. Direct compression

mg /

For 20 g

compressed

mixture

Active ingredient

2.24

0.488 g

Calcium hydrogen phosphate

B.P. *

95.26

19.052 g

Croscarmellose sodium USP

2.00

0.400 g

Magnesium stearate, B.P.

0.50

0.100 g

Weight of tablet

100 mg

* of quality suitable for direct compression.

The active ingredient is sieved before use. Weigh in a clean polythene sachet calcium hydrogen phosphate, croscarmellose sodium and the active ingredient. The powders are mixed by vigorous stirring for 5 minutes. Weigh the magnesium stearate, add it to the mixture and then mix again for 2 minutes. The mixture is then compressed using a Manesty F3 tablet machine with 5.5 mm bevelled edge flat punches to produce tablets for weighing

100 mg. , i.

(Table at the top of the next column)

The active ingredient is sieved through an appropriate sieve and mixed with lactose, starch and pregelatinized corn starch. Appropriate volumes of purified water are added and the powders are granulated. After drying, the granules are sieved and mixed

B. Wet granulation

mg / tablet

Active ingredient

2.24

Lactose B.P.

151.5

Starch B.P.

30.0

B.P.Pregelatinized Corn Starch

15.0

B.P. magnesium stearate

1.5

Weight of tablet

200.0

with magnesium stearate. The granules are then shaped into tablets using punches 7 mm in diameter.

Tablets can be made at other strengths by changing the ratio of the active ingredient to lactose or the weight of the tablets and using appropriate punches.

The tablets can be coated with a film of suitable film-forming materials such as hydroxypropyl methylcellulose, according to conventional techniques. Otherwise, the tablets can be coated.

Capsules

mg / capsule

Active ingredient

28.00

Starch 1500 *

174.00

B.P. magnesium stearate

1.00

Load weight

200.00

* Starch form suitable for direct compression.

The active ingredient is sieved and mixed with the excipients. The mixture is introduced into No. 2 hard gelatin capsules using an appropriate machine. Other doses can also be prepared by modifying the weight of the load and, if necessary, by modifying the size of the capsule as appropriate.

Syrup

mg / 5 ml dose

Active ingredient

28.00

Stamp - Aroma - Colorant 1

Preservative - Thickener r

Sweetener J

Purified water for

5.00 ml

The active ingredient, the buffer, the flavor, the color, the preservative, the thickener and the sweetener are dissolved in a little water, the solution is adjusted to the volume and mixed. The syrup thus prepared is clarified by filtration.

Suspension

mg / 5 ml dose

Active ingredient

28.00

Aluminum monostearate

75.00

Sweetener (

Aroma r qs

Dye J

Fractionated coconut oil qs

5.00 ml

5

10

15

20

25

30

35

40

45

50

55

60

65

17

663 411

The aluminum monostearate is dispersed in approximately 90% of the fractionated coconut oil. The suspension obtained is heated to 115 ° C. with stirring, then cooled. The sweetening agent, flavor and color are added and the active ingredient is appropriately dispersed. The suspension is brought to volume with the rest of the fractionated coconut oil and mixed.

Tablets for oral administration powerful mixer. No. 3 hard gelatin capsules are filled with the powder mixture in a suitable encapsulation machine. The contents of the cartridges are administered using a powder inhaler such as Glaxo Rotahaler.

Dosed pressure aerosol

mg / tablet

Active ingredient

2.24

Lactose B.P.

94.56

Sucrose B.P.

86.7

Hydroxypropylmethylcellulose

15.0

B.P. magnesium stearate

1.5

Weight of tablet

200.00

The active ingredient is sieved with an appropriate sieve and

mixture with lactose, sucrose and hydroxypropylmethylcel-lulose. Appropriate volumes of purified water are added and the powders are granulated. After drying, the granules are shaped into tablets with appropriate punches.

25

Suppositories for rectal administration

Active ingredient 5.6 mg

* Witepsol H15 for 1.0 g

* Brand of Adeps Solidus Ph. Eur.

A suspension of the active ingredient in molten Witepsol 30 is prepared and molds for suppositories of 1 g are filled with an appropriate machine.

Injection for intravenous administration mg / ml 35

1.12 mg q.s. 1.0 ml

Active ingredient

Sodium chloride B.P.

B.P. q.s.p.

Sodium chloride can be added to adjust the tone of the solution and the pH can be adjusted using an acid or an alkali, 40 in order to obtain optimal stability and / or to facilitate the dissolution of the active ingredient. Alternatively, suitable buffer salts can be used.

The solution is prepared, clarified and filled with ampoules of appropriate size which are sealed by melting the glass. The injection is sterilized by heating in an autoclave using one of the 45 suitable cycles. Otherwise, the solution can be sterilized by filtration and packaged in sterile ampoules under aseptic conditions. The solutions can be conditioned in an inert atmosphere of nitrogen or another suitable gas.

For inhalation Inhalation cartridges mg / cartridge 16.8 25.00

Active ingredient (micronized)

Lactose B.P. q.s.p.

The active ingredient is micronized in a fine particle jet mill before mixing with the lactose for tablets in a

mg / dose per box

Active ingredient (micronized) Oleic acid B.P. Trichlorofluoromethane B.P. Dichlorodifluoromethane B.P.

0.560 0.050 22.25 60.90

134.4 mg 12 mg 5.34 g 14.62 g

The active ingredient is micronized in a jet mill to form a fine powder. Oleic acid is mixed with trichlorofluoromethane at a temperature of 10 to 15 ° C and the micronized drug is mixed in this solution with a high shear mixer. The suspension is introduced into aluminum aerosol cans and the appropriate metering valves delivering a dose of 85 mg of suspension are crimped onto the cans, then the cans are filled with the valves with pressure dichlorodifluoromethane.

Test protocol

Determination of DHW0 values and equipment concentration rates

The ECS0 values of the compounds according to the invention and the concentration levels of these compounds with respect to 5-hydroxytrypt-amine are determined by the method described by W. Feniuk, P.P.A. Humphrey and A.D. Watts, in Br. J. Pharmacol., 1980, 73 191P-192P.

Toxicology

The compounds of Examples 1 and 3 were administered to Wistar rats, intraperitoneally, at a dose of 6 mg / kg, and that of Example 10 at doses of 6.25, 12.5 and 25 mg / kg.

Test results

Composed of the example

ECS0 (| iM)

Equipotent concentration rate

1

0.89

1.2

2

0.075

0.9

4

0.12

1.3

5

0.315

1.65

9

0.31

4.7

12

0.17

3.3

14

1.0

3.7

The compounds of Examples 1, 3 and 10 have no toxic effects when administered to rats at the doses described above.

r

Claims (10)

663411 2 1. Compounds of general formula (I): R1R2nso2A \ not / AlkNR3R4 (I) h in which R 1 represents a hydrogen atom or a Q 6 alkyl or C3 6 alkenyl radical; R2 represents a hydrogen atom or a C1-3 alkyl, Q-6j alkenyl phenyl, phenyl-CM alkyl, or C5-7 cycloalkyl radical; R3 and R4, which are identical or different, each represents a hydrogen atom or a Cw or 2-propenyl alkyl radical or R3 and R4 together form an aralkylidene radical; Alk represents an alkylene chain containing two or three carbon atoms which may be unsubstituted or substituted by not more than two C 1 -C 3 alkyl radicals, and A represents an alkylene chain containing 2 to 5 carbon atoms which can be unsubstituted or substituted by no more than two C 1 -C 3 alkyl radicals and their physiologically acceptable salts and their solvates. 2. Compounds of general formula (I) or their physiologically acceptable salts or their solvates according to claim 1 where one of R! and R2 or both represent a hydrogen atom. 3. Compounds of general formula (I) or their physiologically acceptable salts or their solvates according to one of claims 1 or 2 where A and Alk represent unsubstituted alkylene chains. 4. Compounds of general formula (I) or their physiologically acceptable salts or their solvates according to claim 3 wherein Alk represents an unsubstituted alkylene chain containing two carbon atoms. 5. Compounds according to claim 1 of general formula (la): RlaR2aNS02 (CH2> n / H in which RIa represents a hydrogen atom or an alkyl radical in Cl-3-> R2a represents a hydrogen atom or an alkyl radical in CU3 or phenyl-alkyl in C] _2; R3a and R4a, which are identical or different, each represent a hydrogen atom or a methyl or ethyl radical, and n represents 2 or 3, and their physiologically acceptable salts and their solvates. 6. Compounds according to claim 1 of general formula (Ib): RlbNHS02 (CH2) 2 and their physiologically acceptable salts and their solvates. 7. Physiologically acceptable salts of a compound according to one of claims 1 to 6, chosen from hydrochlorides, bromhy- 5 drates, sulfates, fumarates, maleates and succinates. 8. Pharmaceutical composition comprising at least one compound according to one of claims 1 to 6, of general formula (I) or a physiologically acceptable salt or a corresponding solvate with a physiologically acceptable carrier. 9. Pharmaceutical composition according to claim 8 packaged for oral administration. 10. Compounds of general formula (III): r1r2nso2a (III) nhnh- As starting materials in the manufacture of the compounds of general formula (I) according to claim 1, wherein Rb R2 and A are as defined for the general formula (I) of claim 1, as well as their salts. 11. Compounds of general formula (IX): xso2a AlkNR3R4 30 not ^ h (IX) / as starting materials in the manufacture of the compounds of general formula (I) according to claim 1, in which X represents a labile group and A, Alk, R3 and R4 are as defined for 3s the general formula (I) in claim 1 . . <CH2Î2NR3aR4a (the) , (CH2) 2NR3bR4b (Ib) in which Rlb represents a hydrogen atom or a C 3 -C 3 alkyl radical, and R3b and R4b, identical or different, each represent a hydrogen atom or a methyl or ethyl radical,